In addition to raising the titers of specific antibodies secreted by the B-cell population, antigenic foreign substances stimulate responses from the lymphatic T-cell population. In general, there are now considered to be three subpopulations of T-cells-killer (or effector) cells, helper cells, and suppressor cells. Stated in a somewhat oversimplified manner, the helper cell population and the suppressor cell population exert the indicated opposite effects on the effectors and, in particular, on the formation and activity of cytotoxic T-lymphocytes (CTLs).
The suppressor cell population is considered to be to some degree self-regulating, i.e., to include cells which are contrasuppresive. Evidence for contrasuppresive cells has been shown by others, including the demonstration that these cells are involved in localizing the immune response in order to prevent unwanted reactions (Green, D. R., et al, Proc Natl Acad Sci USA (1982) 79: 889; Mattingly, J. A., et al, J Immunol (1978) 121: 1878. Countrasuppressor cells have been implicated as a factor in autoimmune reactions such as in diabetes (Ptak, W., et al, Nature (1980) 283: 199); and in NZB mice (Smith, H. R., et al., J Immunol (1982) 129: 2332). It has also been shown that induction of contrasuppressor cells can be obtained by injection of hapten/IgG mixtures, leading to the destruction of tumors (Hamaoka, T., et al, J Exp Med (1979) 149: 185). Induction of contrasuppressors in vitro and in vivo has been demonstrated by preculturing with antigen alone or in combination with antibodies (Gershon, R. K., et al, J Exp Med (1981) 153: 1533; Green, D. R., et al, NY Acad Sci (1982) 398: 318; Green, D. R., et al, Immunology Today (1986) 7: 181).
A general model for suppressor T-Cell system is shown in the diagram below: ##STR1##
The end products of this cascade, designated in the diagram Ts3 and CS (contrasuppressors), presumably exert opposite effects. That is, the Ts3 cells are putatively effective in suppressing the immune response of the T-Cell system and the contrasuppressors regulate the activity of Ts3 either directly or indirectly. Both of these populations are in some way regulated by or interactive with the anti-idiotypic TsF2 factor secreted by the Ts2 cells of the cascade. The Ts2 cells are stimulated, in turn by TsF1 factors which are idiotypic and are secreted by Ts1 cells, the primary cells interactive with the stimulating antigen.
A murine hybridoma designated A10, which secretes a TsF1 factor in response to the P815 antigen of the corresponding murine tumor and which factor is specific for this antigen was described by Steele, J. K., et al, J Immunol (1985) 134: 2767-2778; and a human counterpart of this TsF1 factor has been found in tonsil cells (Steele, J. K., et al, J Immunol (1985) 135: 1201-1206). A hybridoma secreting a TsF1 specific for the antigen ferredoxin (Fd) is designated Fd11 and is described by Steele, J. K., et al, J Immunol (1986), in press. In addition, a TsF2-secreting cell line designated A29 which is anti-idiotypic with respect to the P815 antigen has also been described (Steele, J. K., et al, J Immunol (1986), in press.
It has also been previously shown that administration of the A10 generated TsF1 intravenously into mice contemporaneously with tumor cell injection enhances the in vivo growth of the P815 tumor specifically, and that the TsF1 is inhibitory to the development of P815-specific CTL's in vitro (Steele, J. K., et al, J Immunol (1985) 134: 2767-2778, supra); Steele, J. K., et al, in Induction and Recognition of the Transformed Cell (1986), Greene, M. I., et al, eds, Plenum Press, New York).
While the suppression of the immune system may be desirable in some cases, such as in the event of autoimmune disease or allergies, in most cases it is desirable to stimulate the ability of the immune system to cope with potentially harmful foreign material such as tumors and infectious organisms. Thus, it is particularly important that it has now been found that by correct timing of the administration of TsF1, rather than promoting the proliferation of invading tumors or pathogens, TsF1 enhances the effectiveness of the immune system against these invaders.